Substituted piperidines as melanocortin receptor agonists

ABSTRACT

Certain novel 4-substituted piperidine compounds are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US01/25757, filed Aug. 17, 2001, now WO02/15909, which claims priority under 35 U.S.C. 119 from U.S.Provisional Application No. 60/227,180, filed Aug. 23, 2000.

SUMMARY OF THE INVENTION

The present invention relates to piperidine derivatives, theirsynthesis, and their use as melanocortin receptor (MC-R) agonists. Moreparticularly, the compounds of the present invention are selectiveagonists of the melanocortin-4 receptor (MC-4R) and are thereby usefulfor the treatment of disorders responsive to the activation of MC-4R,such as obesity, diabetes, and male and/or female sexual dysfunction.

BACKGROUND OF THE INVENTION

Pro-opiomelanocortin (POMC) derived peptides are known to affect foodintake. Several lines of evidence support the notion that the G-proteincoupled receptors (GPCRs) of the melanocortin receptor (MC-R) family,several of which are expressed in the brain, are the targets of POMCderived peptides involved in the control of food intake and metabolism.A specific single MC-R that may be targeted for the control of obesityhas not yet been identified, although evidence has been presented thatMC-4R signalling is important in mediating feed behavior (S. Q. Giraudoet al., “Feeding effects of hypothalamic injection of melanocortin-4receptor ligands,” Brain Research, 80: 302-306 (1998)).

Evidence for the involvement of MC-R's in obesity includes: i) theagouti (A^(vy)) mouse which ectopically expresses an antagonist of theMC-1R, MC-3R and -4R is obese, indicating that blocking the action ofthese three MC-R's can lead to hyperphagia and metabolic disorders; ii)MC-4R Inockout mice (D. Huszar et al., Cell, 88: 131-141 (1997))recapitulate the phenotype of the agouti mouse and these mice are obese;iii) the cyclic heptapeptide MT-II (a non-selective MC-1R, -3R, -4R, and-5R agonist) injected intracerebroventricularly (ICV) in rodents,reduces food intake in several animal feeding models (NPY, ob/ob,agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist;MC-1R and -5R agonist) reverses this effect and can induce hyperphagia;iv) chronic intraperitoneal treatment of Zucker fatty rats with anα-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R,-4R, and -5R and to attenuate food intake and body weight gain over a12-week period (I. Corcos et al., “HP228 is a potent agonist ofmelanocortin receptor-4 and significantly attenuates obesity anddiabetes in Zucker fatty rats,” Society for Neuroscience Abstracts, 23:673 (1997)).

Five distinct MC-R's have thus far been identified, and these areexpressed in different tissues. MC-1R was initially characterized bydominant gain of function mutations at the Extension locus, affectingcoat color by controlling phaeomelanin to eumelanin conversion throughcontrol of tyrosinase. MC-1R is mainly expressed in melanocytes. MC-2Ris expressed in the adrenal gland and represents the ACTH receptor.MC-3R is expressed in the brain, gut, and placenta and may be involvedin the control of food intake and thermogenesis. MC-4R is uniquelyexpressed in the brain, and its inactivation was shown to cause obesity(A. Kask, et al., “Selective antagonist for the melanocortin-4 receptor(HS014) increases food intake in free-feeding rats,” Biochem. Biophys.Res. Commun., 245: 90-93 (1998)). MC-5R is expressed in many tissues,including white fat, placenta and exocrine glands. A low level ofexpression is also observed in the brain. MC-5R knockout mice revealreduced sebaceous gland lipid production (Chen et al., Cell, 91: 789-798(1997)).

Erectile dysfunction denotes the medical condition of inability toachieve penile erection sufficient for successful sexual intercourse.The term “impotence” is oftentimes employed to describe this prevalentcondition. Approximately 140 million men worldwide, and, according to aNational Institutes of Health study, about 30 million American mensuffer from impotency or erectile dysfunction. It has been estimatedthat the latter number could rise to 47 million men by the year 2000.Erectile dysfunction can arise from either organic or psychogeniccauses, with about 20% of such cases being purely psychogenic in origin.Erectile dysfunction increases from 40% at age 40, to 67% at age 75,with over 75% occurring in men over the age of 50. In spite of thefrequent occurrence of this condition, only a small number of patientshave received treatment because existing treatment alternatives, such asinjection therapies, penile prosthesis implantation, and vacuum pumps,have been uniformly disagreeable [for a discussion, see “ABC of sexualhealth—erectile dysfunction,” Brit. Med. J. 318: 387-390 (1999)]. Onlymore recently have more viable treatment modalities become available, inparticular orally active agents, such as sildenafil citrate, marketed byPfizer under the brand name of Viagra®. (See “Emerging pharmacologicaltherapies for erectile dysfunction,” Exp. Opin. Ther. Patents 9:1689-1696 (1999)). Sildenafil is a selective inhibitor of type Vphosphodiesterase (PDE-V), a cyclic-GMP-specific phosphodiesteraseisozyme [see R. B. Moreland et al, “Sildenafil: A Novel Inhibitor ofPhosphodiesterase Type 5 in Human Corpus Cavemosum Smooth Muscle Cells,”Life Sci., 62: 309-318 (1998)]. Prior to the introduction of Viagra onthe market, less than 10% of patients suffering from erectiledysfunction received treatment. Sildenafil is also being evaluated inthe clinic for the treatment of female sexual dysfunction.

The regulatory approval of Viagra® for the oral treatment of erectiledysfunction has invigorated efforts to discover even more effectivemethods to treat erectile dysfunction. Several additional selectivePDE-V inhibitors are in clinical trials. UK-114542 is a sildenafilbackup from Pfizer with supposedly improved properties. IC-351 (ICOSCorp.) is claimed to have greater selectivity for PDE-V over PDE-VI thansildenafil. Other PDE-V inhibitors include M-54033 and M-54018 fromMochida Pharmaceutical Co. and E4010 from Eisai Co., Ltd.

Other pharmacological approaches to the treatment of erectiledysfunction have been described [see, e.g., “Latest Findings on theDiagnosis and Treatment of Erectile Dysfunction,” Drug News &Perspectives, 9: 572-575 (1996); “Oral Pharmacotherapy in ErectileDysfunction,” Current Opinion in Urology, 7: 349-353 (1997)]. A productunder clinical development by Zonagen is an oral formulation of thealpha-adrenoceptor antagonist phentolamine mesylate under the brand nameof Vasomax®. Vasomax® is also being evaluated for the treatment offemale sexual dysfunction.

Drugs to treat erectile dysfunction act either peripherally orcentrally. They are also classified according to whether they “initiate”a sexual response or “facilitate” a sexual response to prior stimulation[for a discussion, see “A Therapeutic Taxonomy of Treatments forErectile Dysfunction: An Evolutionary Imperative,” Int. J. ImpotenceRes., 9: 115-121 (1997)]. While sildenafil and phentolamine actperipherally and are considered to be “enhancers” or “facilitators” ofthe sexual response to erotic stimulation, sildenafil appears to beefficacious in both mild organic and psychogenic erectile dysfunction.Sildenafil has an onset of action of 30-60 minutes after an oral dosewith the effect lasting about 4 hours, whereas phentolamine requires5-30 minutes for onset with a duration of 2 hours. Although sildenafilis effective in a majority of patients, it takes a relatively long timefor the compound to show the desired effects. The faster-actingphentolarmine appears to be less effective and to have a shorterduration of action than sildenafil. Oral sildenafil is effective inabout 70% of men who take it, whereas an adequate response withphentolamine is observed in only 35-40% of patients. Both compoundsrequire erotic stimulation for efficacy. Since sildenafil indirectlyincreases blood flow in the systemic circulation by enhancing the smoothmuscle relaxation effects of nitric oxide, it is contraindicated forpatients with unstable heart conditions or cardiovascular disease, inparticular patients taking nitrates, such as nitroglycerin, to treatangina. Other adverse effects associated with the clinical use ofsildenafil include headache, flushing, dyspepsia, and “abnormal vision,”the latter the result of inhibition of the type VI phosphodiesteraseisozyme (PDE-VI), a cyclic-GMP-specific phosphodiesterase that isconcentrated in the retina. “Abnormal vision” is defined as a mild andtransient “bluish” tinge to vision, but also an increased sensitivity tolight or blurred vision.

Synthetic melanocortin receptor agonists (melanotropic peptides) havebeen found to initiate erections in men with psychogenic erectiledysfunction [See H. Wessells et al., “Synthetic Melanotropic PeptideInitiates Erections in Men With Psychogenic Erectile Dysfunction:Double-Blind, Placebo Controlled Crossover Study,” J. Urol., 160:389-393 (1998); Fifteenth American Peptide Symposium, Jun. 14-19, 1997(Nashville Tenn.)]. Activation of melanocortin receptors of the brainappears to cause normal stimulation of sexual arousal. In the abovestudy, the centrally acting α-melanocyte-stimulating hormone analog,melanotan-II (MT-II), exhibited a 75% response rate, similar to resultsobtained with apomorphine, when injected intramuscularly orsubcutaneously to males with psychogenic erectile dysfunction. MT-II isa synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH₂,which contains the 4-10 melanocortin receptor binding region common toα-MSH and adrenocorticotropin, but with a lactam bridge. It is anon-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., LifeSciences, Vol. 58, 1777-1784, 1996). MT-II (also referred to as PT-14)(Erectide®) is presently in clinical development by PalatinTechnologies, Inc. and TheraTech, Inc. as a non-penile subcutaneousinjection formulation. It is considered to be an “initiator” of thesexual response. The time to onset of erection with this drug isrelatively short (10-20 minutes) with a duration of action approximately2.5 hours. Adverse reactions observed with MT-II include nausea,flushing, loss of appetite, stretching, and yawning and may be theresult of activation of MC-1R; MC-2R, MC-3R, and/or MC-5R. MT-II must beadministered parenterally, such as by subcutaneous, intravenous, orintramuscular route, since it is not absorbed into the systemiccirculation when given by the oral route. Compositions of melanotropicpeptides and methods for the treatment of psychogenic erectiledysfunction are disclosed in U.S. Pat. No. 5,576,290, assigned toCompetitive Technologies. Methods of stimulating sexual response infemales using melanotropic peptides have been disclosed in U.S. Pat. No.6,051,555.

A series of spiropiperidine derivatives has been disclosed in WO99/64002 (published Dec. 16, 1999) as agonists of the melanocortinreceptor(s) and thereby useful for the treatment of diseases anddisorders, such as obesity, diabetes, and sexual dysfunction, includingerectile dysfunction and female sexual dysfunction.

Because of the unresolved deficiencies of the various pharmacologicalagents discussed above, there is a continuing need in the medical artsfor improved methods and compositions to treat individuals sufferingfrom psychogenic and/or organic erectile dysfunction. Such methodsshould have wider applicability, enhanced convenience and ease ofcompliance, short onset of action, reasonably long duration of action,and minimal side effects with few contraindications, as compared toagents now available.

It is therefore an object of the present invention to provide compoundswhich are melanocortin receptor agonists and thereby useful to treatobesity, diabetes, and male and/or female sexual dysfunction.

It is another object of the present invention to provide compounds whichare selective agonists of the melanocortin-4 (MC-4R) receptor.

It is another object of the present invention to provide pharmaceuticalcompositions comprising the compounds which are melanocortin receptoragonists.

It is another object of the present invention to provide methods for thetreatment or prevention of disorders, diseases, or conditions responsiveto the activation of the melanocortin receptor in a subject in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

It is another object of the present invention to provide compounds andpharmaceutical compositions useful for the treatment or prevention ofobesity, diabetes mellitus, and male and/or female sexual dysfunction.

It is another object of the present invention to provide compounds andpharmaceutical compositions for the treatment or prevention of erectiledysfunction.

It is another object of the present invention to provide methods for thetreatment or prevention of obesity, diabetes mellitus, and male and/orfemale sexual dysfunction.

These and other objects will become readily apparent from the detaileddescription that follows.

SUMMARY OF THE INVENTION

The present invention relates to novel 4-substituted piperidines ofstructural formula I:

wherein

Q is

These piperidine derivatives are effective as melanocortin receptoragonists and are particularly effective as selective melanocortin-4receptor (MC-4R) agonists. They are therefore useful for the treatmentand/or prevention of disorders responsive to the activation of MC-4R,such as obesity, diabetes as well as male and/or female sexualdysfunction, in particular, male erectile dysfunction.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment orprevention of disorders, diseases, or conditions responsive to theactivation of the melanocortin receptor in a subject in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention.

The present invention also relates to methods for the treatment orprevention of obesity, diabetes mellitus, and male and/or female sexualdysfunction by administering the compounds and pharmaceuticalcompositions of the present invention.

The present invention also relates to methods for treating erectiledysfunction by administering the compounds and pharmaceuticalcompositions of the present invention.

The present invention also relates to methods for treating erectiledysfunction by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention also relates to methods for treating or preventingobesity by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 4-substituted piperidines useful asmelanocortin receptor agonists, in particular, as selective MC-4Ragonists. Representative compounds of the present invention aredescribed by structural formula (I):

wherein

Q is

Cy is selected from the group consisting of

aryl,

5- or 6-membered heteroaryl,

5- or 6-membered heterocyclyl, and

5- to 7-membered carbocyclyl;

wherein Cy is substituted with one to three groups independentlyselected from R³;

A is O, S(O)_(m), NR⁷, or CH₂;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1 or 2;

q is 0, 1 or 2;

r is 1, 2, or 3;

R¹ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

(CHR⁷)_(n)—C₃₋₇ cycloalkyl,

(CHR⁷)_(n)aryl, and

(CHR⁷)_(n)heteroaryl;

in which aryl and heteroaryl are unsubstituted or substituted with oneto three groups independently selected from R⁶; and alkyl and cycloalkylare unsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo;

R² is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₇ cycloalkyl, and

(CH₂)_(n)-aryl;

each R³ is independently selected from

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)-aryl,

(CH₂)_(n)C₃₋₇ cycloalkyl,

(CH₂)_(n)-heteroaryl,

halo,

OR⁷,

NHSO₂R⁷,

N(R⁷)₂,

C≡N,

CO₂R⁷,

C(R⁷)(R⁷)N(R⁷)₂,

NO₂,

SO₂N(R⁷)₂,

S(O)_(m)R⁷,

CF₃, and

OCF₃;

R⁴ and R⁵ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl, and

C₃₋₈ cycloalkyl;

or R⁴ and R⁵ together with the nitrogen to which they are attached forma 5- to 8-membered ring optionally containing an additional heteroatomselected from O, S, and NR⁷;

wherein alkyl and cycloalkyl are unsubstituted or substituted with oneto three groups independently selected from R⁶ and oxo;

R⁶ is selected from the group consisting of

 C₁₋₈ alkyl,

 (CH₂)_(n)-aryl,

 (CH₂)_(n)C₃₋₇ cycloalkyl,

 (CH₂)_(n)-heteroaryl,

 halo,

 OR⁷,

 NHSO₂R⁷,

 N(R⁷)₂,

 C≡N,

 CO₂R⁷,

 C(R⁷)(R⁷)N(R⁷)₂,

 NO₂,

 SO₂N(R⁷)₂,

 S(O)_(m)R⁷,

 CF₃, and

 OCF₃;

each R⁷ is independently selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)-aryl, and

(CH₂)_(n)C₃₋₇ cycloalkyl;

each R⁸ is independently selected from the group consisting of

hydrogen,

C₁₋₈alkyl,

(CH₂)_(n)-aryl,

(CH₂)_(n)-heteroaryl, and

(CH₂)_(n)C₃₋₇ cycloalkyl;

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups independently selected from R⁶; and alkyl, cycloalkyl, and(CH₂)_(n) are unsubstituted or substituted with one to three groupsindependently selected from R⁶ and oxo; or two R⁸ groups together withthe atoms to which they are attached form a 5- to 8-membered mono orbi-cyclic ring system optionally containing an additional heteroatomselected from O, S, and NR⁷;

X is selected from the group consisting of

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₈ cycloalkyl,

(CH₂)_(n)aryl,

(CH₂)_(n)heteroaryl,

(CH₂)_(n)heterocyclyl,

(CH₂)_(n)C≡N,

(CH₂)_(n)CON(R⁸R⁸),

(CH₂)_(n)CO₂R⁸,

(CH₂)_(n)COR⁸

(CH₂)_(n)NR⁸C(O)R⁸,

(CH₂)_(n)NR⁸CO₂R⁸,

(CH₂)_(n)NR⁸C(O)N(R⁸)₂,

(CH₂)_(n)NR⁸SO₂R⁸,

(CH₂)_(n)S(O)_(m)R⁸,

(CH₂)_(n)SO₂N(R⁸)(R⁸),

(CH₂)_(n)OR⁸,

(CH₂)_(n)OC(O)R⁸,

(CH₂)_(n)OC(O)OR⁸,

(CH₂)_(n)OC(O)N(R⁸)₂,

(CH₂)_(n)N(R⁸)(R⁸), and

(CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸);

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), cycloalkyl, andheterocyclyl are unsubstituted or substituted with one to four groupsindependently selected from R⁶ and oxo;

Y is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₈ cycloalkyl,

(CH₂)_(n)aryl,

(CH₂)_(n)heterocyclyl, and

(CH₂)_(n)heteroaryl;

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶, and alkyl, (CH₂)_(n), cycloalkyl, andheterocyclyl are optionally substituted with one to three groupsselected from R⁶ and oxo;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compounds of formula I, Cy is selected from thegroup consisting of benzene, pyridine, pyrazine, piperidine, andcyclohexane. In a class of this embodiment, Cy is benzene orcyclohexane; in a subclass of this class, Cy is benzene.

In another embodiment of the compounds of formula I, R¹ is CH(R⁷)-arylor CH(R⁷)-heteroaryl wherein aryl and heteroaryl are optionallysubstituted with one or two R⁶ groups. In a class of this embodiment, R¹is benzyl optionally substituted with one or two groups selected fromhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, and OCF₃. In a subclass of thisclass, R¹ is 4-chlorobenzyl, 4-fluorobenzyl, or 4-methoxybenzyl.

In a third embodiment of compounds of formula I, R² is H or CH₃.

In a fourth embodiment of compounds of formula I, X is (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)C(O)N(R⁸)(R⁸),(CH₂)_(n)CO₂R⁸, (CH₂)_(n)OR⁸, (CH₂)_(n)NR⁸C(O)R⁸, or (CH2)nNR⁸SO₂R⁸,wherein aryl and heteroaryl are optionally substituted with one to threegroups selected from R⁶; heterocyclyl is optionally substituted with oneto three groups selected from R⁶ and oxo; and the (CH₂)_(n) group isoptionally substituted with one to three groups selected from R⁷, halo,S(O)_(m)R⁷, N(R⁷)₂, and OR⁷. In a class of this embodiment, X isCH₂-heteroaryl, CH₂-heterocyclyl, NHC(O)R⁸, CO₂R⁸, or C(O)N(R⁸)(R⁸),wherein heteroaryl is optionally substituted with one to three groupsselected from R⁶; heterocyclyl is optionally substituted with one tothree groups selected from R⁶ and oxo; and wherein R⁸ is eachindependently selected from H and C₁₋₆ alkyl optionally substituted withOR⁷, SR⁷, or N(R⁷)₂, or 2 R⁷ groups together with the nitrogen to whichthey are attached form a 5- or 6-membered ring optionally having anadditional heteroatom selected from O, S and NR⁷. In a subclass of thisclass, heteroaryl is selected from the group consisting of pyridyl,pyrazinyl, pynmidinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl,pyrazolyl, and imidazolyl.

In a fifth embodiment of compounds of formula I, Y is C₁₋₈ alklyl,(CH₂)_(n)C₅₋₇ cycloalkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heterocyclyl or(CH₂)_(n)-heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one to three groups selected from R⁶; and (CH₂)_(n),alkyl, cycloalkyl, and heterocyclyl are optionally substituted with oneto three groups selected from R⁶ and oxo. In a class of this embodiment,Y is cyclohexyl, cycloheptyl, cyclopentyl, phenyl, or C₁₋₆ alkyl,unsubstituted or substituted with one to three groups selected from R⁶and oxo. In a subclass of this class, Y is cyclohexyl or C₁₋₆ alkyl,wherein the cyclohexyl and alkyl groups are unsubstituted or substitutedwith one to three groups selected from R⁶ and oxo.

In a sixth embodiment of compounds of formula I, q is 1 and p is 0, 1,or 2; in a class of this embodiment, p and q are both 1.

In a yet a further embodiment there are provided compounds of formulaIa:

wherein

Cy is phenyl or cyclohexyl,

wherein Cy is substituted with one to three groups independentlyselected from R³;

n is 0 or 1;

p is 0, 1, or 2;

R² is selected from the group consisting of

hydrogen,

C₁₋₆ alkyl, and

C₅₋₆ cycloalkyl;

each R³ is independently selected from

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)-aryl,

(CH₂)_(n)C₃₋₇ cycloalkyl,

(CH₂)_(n)-heteroaryl,

halo,

OR⁷,

NHSO₂R⁷,

N(R⁷)₂,

C≡N,

CO₂R⁷,

C(R⁷)(R⁷)N(R⁷)₂,

NO₂,

SO₂N(R⁷)₂,

S(O)_(m)R⁷,

CF₃, and

OCF₃;

R⁴ and R⁵ are each independently selected from the group consisting of

hydrogen,

C₁₋₆ alkyl, and

C₅₋₆ cycloalkyl;

or R⁴ and R⁵ together with the nitrogen to which they are attached forma 5- to 8-membered ring, optionally containing an additional heteroatomselected from O, S, and NR⁷;

wherein alkyl and cycloalkyl are unsubstituted or substituted with oneto three groups independently selected from R⁶ and oxo;

R⁶ is selected from the group consisting of

C₁₋₈ alkyl,

(CH₂)_(n)-aryl,

(CH₂)_(n)C₃₋₇cycloalkyl,

(CH₂)_(n)-heteroaryl,

halo,

OR⁷,

NHSO₂R⁷,

N(R⁷)₂,

C≡N,

CO₂R⁷,

C(R⁷)(R⁷)N(R⁷)₂,

NO₂,

SO₂N(R⁷)₂,

S(O)_(m)R⁷,

CF₃, and

OCF₃;

each R⁷ is independently selected from the group consisting of

hydrogen,

C₁₋₈ alky, and

C₃₋₆ cycloalkyl;

each R⁸ is independently selected from the group consisting of

hydrogen,

C₁₋₅ alkyl,

aryl,

heteroaryl, and

C₅₋₆cycloalkyl;

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups independently selected from R⁶; and alkyl and cycloalkylare unsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; or two R⁸ groups together with the atoms towhich they are attached form a 5- to 8-membered mono- or bi-cyclic ringoptionally containing an additional heteroatom selected from O, S, andNR⁷;

X is selected from the group consisting of

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₈cycloalkyl,

(CH₂)_(n)aryl,

(CH₂)_(n)heteroaryl,

(CH₂)_(n)heterocyclyl,

(CH₂)_(n)C≡N,

(CH₂)_(n)CON(R⁸R⁸),

(CH₂)_(n)CO₂R⁸,

(CH₂)_(n)COR⁸

(CH₂)_(n)NR⁸C(O)R⁸,

(CH₂)_(n)NR⁸CO₂R⁸,

(CH₂)_(n)NR⁸C(O)N(R⁸)₂,

(CH₂)_(n)NR⁸SO₂R⁸,

(CH₂)_(n)S(O)mR⁸,

(CH₂)_(n)SO₂N(R⁸)(R⁸),

(CH₂)_(n)OR⁸,

(CH₂)_(n)OC(O)R⁸,

(CH₂)_(n)OC(O)OR⁸,

(CH₂)_(n)OC(O)N(R⁸)₂,

(CH₂)_(n)N(R⁸)(R⁸), and

(CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸);

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), cycloalkyl, andheterocyclyl are unsubstituted or substituted with one to four groupsindependently selected from R⁶ and oxo;

Y is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₆ cycloalkyl,

(CH₂)_(n)aryl, and

(CH₂)_(n)heteroaryl;

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), and cycloalkyl areunsubstituted or substituted with one to three groups selected from R⁶and oxo; or a pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula Ia, the carbon atom markedwith * has the R configuration.

In a second embodiment of compounds of formula Ia, X is selected fromthe group consisting of:

Representative compounds of formula Ia are as follows:

or a pharmaceutically acceptable salt thereof.

In a yet a further embodiment of the compounds of the present invention,there are provided compounds of formula Ib:

wherein

Cy is phenyl or cyclohexyl,

wherein Cy is substituted with one to three groups independentlyselected from R³;

n is 1 or 2;

R² is selected from the group consisting of

hydrogen,

C₁₋₆ alkyl, and

C₅₋₆ cycloalkyl;

each R³ is independently selected from

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)-aryl,

(CH₂)_(n)C₃₋₇ cycloalkyl,

(CH₂)_(n)-heteroaryl,

halo,

OR⁷,

NHSO₂R⁷,

N(R⁷)₂,

C≡N,

CO₂R⁷,

C(R⁷)(R⁷)N(R⁷)₂,

NO₂,

SO₂N(R⁷)₂,

S(O)_(m)R⁷,

CF₃, and

OCF₃;

R⁴ and R⁵ are each independently selected from the group consisting of

hydrogen,

C₁₋₆ alkyl, and

C₅₋₆ cycloalkyl;

or R⁴ and R⁵ together with the nitrogen to which they are attached forma 5- to 8-membered ring optionally containing an additional heteroatomselected from O, S, and NR⁷;

wherein alkyl and cycloalkyl are unsubstituted or substituted with oneto three groups independently selected from R⁶ and oxo;

R⁶ is selected from the group consisting of

C₁₋₈ alkyl,

(CH₂)_(n)-aryl,

(CH₂)_(n)C₃₋₇cycloalkyl,

(CH₂)_(n)-heteroaryl,

halo,

OR⁷,

NHSO₂R⁷,

N(R⁷)₂,

C≡N,

CO₂R⁷,

C(R⁷)(R⁷)N(R⁷)₂,

NO₂,

SO₂N(R⁷)₂,

S(O)_(m)R⁷,

CF₃, and

OCF₃;

each R⁷ is independently selected from the group consisting of

hydrogen,

C₁₋₈ alky, and

C₃₋₆ cycloalkyl;

each R⁸ is independently selected from the group consisting of

hydrogen,

C₁₋₅ alkyl,

aryl,

heteroaryl, and

C₅₋₆ cycloalkyl;

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups independently selected from R⁶; and alkyl and cycloalkylare unsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; or two

R⁸ groups together with the atoms to which they are attached form a 5-to 8-membered mono- or bi-cyclic ring optionally containing anadditional heteroatom selected from O, S, and NR⁷;

R⁹ is hydrogen or C₁₋₄ alkyl;

X is selected from the group consisting of

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₈cycloalkyl,

(CH₂)_(n)aryl,

(CH₂)_(n)heteroaryl,

(CH₂)_(n)heterocyclyl,

(CH₂)_(n)C≡N,

(CH₂)_(n)CON(R⁸R⁸),

(CH₂)_(n)CO₂R⁸,

(CH₂)_(n)COR⁸

(CH₂)_(n)NR⁸C(O)R⁸,

(CH₂)_(n)NR⁸CO₂R⁸,

(CH₂)_(n)NR⁸C(O)NR⁸)₂,

(CH₂)_(n)NR⁸SO₂R⁸,

(CH₂)_(n)S(O)mR⁸,

(CH₂)_(n)SO₂N(R⁸)(R⁸),

(CH₂)_(n)OR⁸,

(CH₂)_(n)OC(O)R⁸,

(CH₂)_(n)OC(O)OR⁸,

(CH₂)_(n)OC(O)N(R⁸)₂,

(CH₂)_(n)N(R⁸)(R⁸), and

(CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸);

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), cycloalkyl, andheterocyclyl are unsubstituted or substituted with one to four groupsindependently selected from R⁶ and oxo;

Y is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

(CH₂)_(n)C₃₋₆ cycloalkyl,

(CH₂)_(n)aryl, and

(CH₂)_(n)heteroaryl;

wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), and cycloalkyl areunsubstituted or substituted with one to three groups selected from R⁶and oxo; or a pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula Ib, the carbon atom markedwith * has the R configuration.

In a second embodiment of the compounds of formula Ib, X is selectedfrom the group consisting of:

Representative compounds of formula Ib are the following:

or a pharmaceutically acceptable salt thereof.

The compounds of structural Formula I are effective as melanocortinreceptor agonists and are particularly effective as selective agonistsof MC-4R. They are therefore useful for the treatment and/or preventionof disorders responsive to the activation of MC-4R, such as obesity,diabetes as well as male and/or female sexual dysfunction, inparticular, erectile dysfunction, and further in particular, maleerectile dysfunction.

Another aspect of the present invention provides a method for thetreatment or prevention of obesity or diabetes in a subject in needthereof which comprises administering to said subject a therapeuticallyor prophylactically effective amount of a compound of formula I.

Another aspect of the present invention provides a method for thetreatment or prevention of male or female sexual dysfunction includingerectile dysfunction which comprises administering to a subject in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a compound of formula I.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formula I and a pharmaceuticallyacceptable carrier.

Yet another aspect of the present invention provides a method for thetreatment or prevention of male or female sexual dysfunction includingerectile dysfunction which comprises administering to a subject in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a compound of formula I in combination with atherapeutically effective amount of another agent known to be useful forthe treatment of these conditions.

Throughout the instant application, the following terms have theindicated meanings:

The alkyl groups specified above are intended to include those alkylgroups of the designated length in either a straight or branchedconfiguration. Exemplary of such allyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl,isohexyl, and the like.

The term “halogen” is intended to include the halogen atoms fluorine,chlorine, bromine and iodine.

The term “aryl” includes phenyl and naphthyl.

The term “heteroaryl” includes mono- and bicyclic aromatic ringscontaining from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. “5- or 6-membered heteroaryl” are monocyclic heteroaromaticrings, examples thereof include thiazole, oxazole, thiophene, furan,pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole,tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, andthe like. Bicyclic heteroaromatic rings include, but are not limited to,benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole,benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole,isoquinoline, purine, furopyridine and thienopyridine.

The term “5- or 6-membered carbocyclyl” is intended to includenon-aromatic rings containing only carbon atoms such as cyclopentyl andcyclohexyl.

The term “5 and 6-membered heterocyclyl” is intended to includenon-aromatic heterocycles containing one to four heteroatoms selectedfrom nitrogen, oxygen and sulfur. Examples of a 5 or 6-memberedheterocyclyl include piperidine, morpholine, thiamorpholine,pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other; thus for example, NR⁷R⁷ may represent NH₂,NHCH₃, N(CH₃)CH₂CH₃, and the like.

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

“Erectile dysfunction” is a disorder involving the failure of a malemammal to achieve erection, ejaculation, or both. Symptoms of erectiledysfunction include an inability to achieve or maintain an erection,ejaculatory failure, premature ejaculation, or inability to achieve anorgasm. An increase in erectile dysfunction is often associated with ageand is generally caused by a physical disease or as a side-effect ofdrug treatment.

By a melanocortin receptor “agonist” is meant an endogenous or drugsubstance or compound that can interact with a melanocortin receptor andinitiate a pharmacological response characteristic of the melanocortinreceptor. By a melanocortin receptor “antagonist” is meant a drug or acompound that opposes the melanocortin receptor-associated responsesnormally induced by another bioactive agent. The “agonistic” propertiesof the compounds of the present invention were measured in thefunctional assay described below. The functional assay discriminates amelanocortin receptor agonist from a melanocortin receptor antagonist.

By “binding affinity” is meant the ability of a compound/drug to bind toits biological target, in the the present instance, the ability of acompound of formula I to bind to a melanocortin receptor. Bindingaffinities for the compounds of the present invention were measured inthe binding assay described below and are expressed as IC₅₀'s.

“Efficacy” describes the relative intensity with which agonists vary inthe response they produce even when they occupy the same number ofreceptors and with the same affinity. Efficacy is the property thatenables drugs to produce responses. Properties of compounds/drugs can becategorized into two groups, those which cause them to associate withthe receptors (binding affinity) and those that produce a stimulus(efficacy). The term “efficacy” is used to characterize the level ofmaximal responses induced by agonists. Not all agonists of a receptorare capable of inducing identical levels of maximal responses. Maximalresponse depends on the efficiency of receptor coupling, that is, fromthe cascade of events, which, from the binding of the drug to thereceptor, leads to the desired biological effect.

The functional activities expressed as EC₅₀'s and the “agonist efficacy”for the compounds of the present invention at a particular concentrationwere measured in the functional assay described below.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I contain one or more asymmetric centers and canthus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers such asketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase.

Alternatively, any diastereomer of a compound of the general Formula Ior Ia may be obtained by stereospecific synthesis using optically purestarting materials or reagents of known configuration.

Salts

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Salts of basiccompounds encompassed within the term “pharmaceutically acceptablesalts” refer to non-toxic salts of the compounds of this invention whichare generally prepared by reacting the free base with a suitable organicor inorganic acid. Representative salts of basic compounds of thepresent invention include, but are not limited to, the following:acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof include, but are not limited to, salts derived frominorganic bases including aluminum, ammonium, calciumn, copper, ferric,ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium,zinc, and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, cyclic amines, and basicion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobrornine, triethylamine, trimethylarine, tripropylamine,tromethamine, and the like.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Utility

Compounds of formula I are melanocortin receptor agonists and as suchare useful in the treatment, control or prevention of diseases,disorders or conditions responsive to the activation of one or more ofthe melanocortin receptors including, but are not limited to, MC-1,MC-2, MC-3, MC-4, or MC-5. Such diseases, disorders or conditionsinclude, but are not limited to, obesity (by reducing appetite,increasing metabolic rate, reducing fat intake or reducing carbohydratecraving), diabetes mellitus (by enhancing glucose tolerance, decreasinginsulin resistance), hypertension, hyperlipidemia, osteoarthritis,cancer, gall bladder disease, sleep apnea, depression, anxiety,compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain,male and female sexual dysfunction (including impotence, loss of libidoand erectile dysfunction), fever, inflammation, immunemodulation,rheumatoid arthritis, skin tanning, acne and other skin disorders,neuroprotective and cognitive and memory enhancement including thetreatment of Alzheimer's disease. Some compounds encompassed by formulaI show highly selective affinity for the melanocortin-4 receptorrelative to MC-1R, MC-2R, MC-3R, and MC-5R, which makes them especiallyuseful in the prevention and treatment of obesity, as well as maleand/or female sexual dysfunction, including erectile dysfunction.

Administration and Dose Ranges

The term “therapeutically effective amount” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal, or human that isbeing sought by a researcher, veterinarian, medical doctor, or otherclinician. The term “prophylactically effective amount” is intended tomean that amount of a pharmaceutical drug that will prevent or reducethe risk of occurrence of the biological or medical event that is soughtto be prevented in a tissue, a system, animal, or human that is beingsought by a researcher, veterinarian, medical doctor, or otherclinician.

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula I are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.The dosage regimen will also be selected in accordance with the type,species, age, weight, and sex of the subject to be treated. Such dosagemay be ascertained readily by a person skilled in the art.

The term “subject” includes mammals, especially humans, who take amelanocortin receptor agonist of the present invention. Administering ofthe drug to the subject includes both self-administration andadministration to the subject by another person.

When treating obesity, in conjunction with diabetes and/orhyperglycemia, or alone, generally satisfactory results are obtainedwhen the compounds of the present invention are administered at a dailydosage of from 0.01 milligram to about 100 milligrams per kilogram ofanimal body weight, preferably given in a single dose or in divideddoses two to six times a day, or in sustained release form. In the caseof a 70 kg adult human, the total daily dose will generally be fromabout 0.7 milligrams to about 3500 milligrams. This dosage regimen maybe adjusted to provide the optimal therapeutic response.

When treating diabetes mellitus and/or hyperglycemia, as well as otherdiseases or disorders for which compounds of formula I are useful,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.001milligram to about 100 milligram per kilogram of animal body weight,preferably given in a single dose or in divided doses two to six times aday, or in sustained release form. In the case of a 70 kg adult human,the total daily dose will generally be from about 0.07 milligrams toabout 350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

For the treatment of sexual dysfunction compounds of the presentinvention are given in a dose range of 0.001 milligram to about 100milligram per kilogram of body weight, preferably as a single doseorally or as a nasal spray.

Combination Therapy

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I. Examples of other activeingredients that may be combined with a compound of Formula I, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to:

(a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,BRL49653 and the like), and compounds disclosed in WO97/27857, 97/28115,97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;

(b) insulin or insulin mimetics;

(c) sulfonylureas, such as tolbutamide and glipizide;

(d) α-glucosidase inhibitors (such as acarbose),

(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(Oovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, andother statins), (ii) sequestrants (cholestyramine, colestipol and adialkylaminoalkyl derivatives of a cross-linked dextran), (ii) nicotinylalcohol nicotinic acid or a salt thereof, (iii) proliferator-activaterreceptor a agonists such as fenofibric acid derivatives (gemfibrozil,clofibrate, fenofibrate and benzafibrate), (iv) inhibitors ofcholesterol absorption for example beta-sitosterol and (acylCoA:cholesterol acyltransferase) inhibitors for example melinamide, (v)probucol, (vi) vitamin E, and (vii) thyromimetics;

(f) PPARδ agonists, such as those disclosed in WO97/28149;

(g) antiobesity compounds, such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, or β₃ adrenergic receptor agonists;

(h) feeding behavior modifying agents, such as neuropeptide Yantagonists (e.g. neuropeptide Y5) such as those disclosed in WO97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;

(i) PPARα agonists such as described in WO 97/36579 by Glaxo;

(j) PPARγ antagonists as described in WO97/10813;

(k) serotonin reuptake inhibitors such as fluoxetine and sertraline;

(l) growth hormone secretagogues such as MK-0677; and

(m) agents useful in the treatment of male and/or female sexualdysfunction, such as type V cyclic-GMP-specific phosphodiesterase(PDE-V) inhibitors, such as sildenafil and IC-351, and α₂-adrenergicreceptor antagonists, such as phentolamine mesylate, and a dopaminergiccompound, such as apomorphine.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I as an activeingredient or a pharmaceutically acceptable salt thereof, and may alsocontain a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients. The term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicbases or acids including inorganic bases or acids and organic bases oracids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula I may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of Formula I of the present invention can be preparedaccording to the procedures of the following Schemes and Examples, usingappropriate materials and are further exemplified by the followingspecific examples. Moreover, by utilizing the procedures described indetail in PCT International Application Publication No. WO 99/64002,published Dec. 16, 1999, which is incorporated by reference herein inits entirety, in conjunction with the disclosure contained herein, oneof ordinary skill in the art can readily prepare additional compounds ofthe present invention claimed herein. The compounds illustrated in theexamples are not, however, to be construed as forming the only genusthat is considered as the invention. The Examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. The instant compounds aregenerally isolated in the form of their pharmaceutically acceptablesalts, such as those described previously hereinabove. The free aminebases corresponding to the isolated salts can be generated byneutralization with a suitable base, such as aqueous sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide, and potassiumhydroxide, and extraction of the liberated amine free base into anorganic solvent followed by evaporation. The amine free base isolated inthis manner can be further converted into another pharmaceuticallyacceptable salt by dissolution in an organic solvent followed byaddition of the appropriate acid and subsequent evaporation,precipitation, or crystallization. All temperatures are degrees Celsiusunless otherwise noted.

The phrase “standard peptide coupling reaction conditions” meanscoupling a carboxylic acid with an amine using an acid activating agentsuch as EDC, DCC, and BOP in an inert solvent such as dichloromethane inthe presence of a catalyst such as HOBT. The use of protecting groupsfor the amine and carboxylic acid functionalities to facilitate thedesired reaction and minimize undesired reactions is well documented.Conditions required to remove protecting groups are found in standardtextbooks such as Greene, T, and Wuts, P. G. M., Protective Groups inOrganic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. CBZand BOC are commonly used protecting groups in organic synthesis, andtheir removal conditions are known to those skilled in the art. Forexample, CBZ may be removed by catalytic hydrogenation in the presenceof a noble metal or its oxide such as palladium on activated.carbon in aprotic solvent such as methanol or ethanol. In cases where catalytichydrogenation is contraindicated due to the presence of other.potentially reactive functionalities, removal of CBZ groups can also beachieved by treatment with a solution of hydrogen bromide in acetic acidor by treatment with a mixture of TFA and dimethylsulfide. Removal ofBOC protecting groups is carried out with a strong acid, such astrifluoroacetic acid, hydrochloric acid, or hydrogen chloride gas, in asolvent such as methylene chloride, methanol, or ethyl acetate.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention

BOC (boc) t-butyloxycarbonyl BOPbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateBu butyl calc. calculated CBZ (Cbz) benzyloxycarbonyl c-hex cyclohexylc-pen cyclopentyl c-pro cyclopropyl DEAD diethyl azodicarboxylate DIEAdiisopropylethylamine DMAP 4-dimethylaminopyridine DMFN,N-dimethylformamide EDC 1-(3-dimethylaminopropyl)3-ethylcarbodiimideHCl eq. equivalent(s) ESI-MS electron spray ion-mass spectroscopy Etethyl EtOAc ethyl acetate HATUN-[(diethylamino)-1H-1,2,3-triazolo[4,5-b] pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HOAt1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole hydrate HPLChigh performance liquid chromatography LDA lithium diisopropylamideMC-xR melanocortin receptor (x being a number) Me methyl MF molecularformula Ms methanesulfonyl NMM N-methylmorpholine Ph phenyl Phephenylalanine Pr propyl prep. prepared PyBropbromo-tris-pyrrolidino-phosphonium hexafluorophosphate r.t. roomtemperature TFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layerchromatography

Compounds of formula I wherein R⁴ and R⁵ are hydrogen may be prepared asshown in Scheme 1 by coupling intermediates of formula 1 with protectedamino acids of formula 2 or 3 (PG represents a protecting group such asBoc, CBZ, FMOC, Alloc, etc.) employing standard peptide couplingreaction conditions followed by cleavage of the protecting group PG. Theintermediates of formulae 1-3 are synthesized from commerciallyavailable materials by methods well-known to one skilled in the art orby methods outlined below. The preparation of intermediates of formula 1has also been disclosed in WO 00/00000, which is incorporated byreference herein in its entirety. The following section providesillustrative procedures for preparing intermediates of formulae 1-3useful in the preparation of compounds of the present invention. It isto be appreciated that the choice of reagents, solvents, and reactionconditions, and the like may be varied, and the selection of variablesis within the skills of one of ordinary skill in the art.

Compounds of formula I wherein R⁴ and/or R⁵ are other than hydrogen canbe prepared from a compound of formula I wherein R⁴ and R⁵ are hydrogenby reductive amination to introduce an alkyl or substituted alkyl group,or by acylation, sulfonylation, or coupling with protected amino acids.If a protected amino acid is used, deprotection is carried out toliberate the amine functionality.

Preparation of Intermediates

Intermediate 1

To a solution of indene (4.0 g, 34.4 mmol) in ether (40 ml) was added asolution of chlorosulfonyl isocyanate (3.0 ml, 34.4 mmol) in ether (40ml). After stirring at 0° C. for 0.5 hour, the reaction mixture wasallowed to warm up to room temperature and allowed to stir for another 4hours. The reaction mixture was poured into 20% aqueous sodium sulfite(80 ml) and stirred vigorously for one hour. After addition of ethylacetate, the organic layer was separated and the aqueous phase wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine, dried over Na₂SO₄ and concentrated to give thetitle compound as a white solid (3.4 g).

ESI-MS: calc. for C₁₀H₉NO: 159.1; Found: 160 (M+H), 182 (M+Na).

Intermediate 2

To a solution of Intermediate 1 (3.4 g, 21.4 mmol) in dichloromethane(150 ml) were added triethylamine (8.9 ml, 64.2 mmol),4-dimethylaminopyridine (0.26 g, 2.14 mmol) and di-tert-butyldicarbonate (5.1 g, 23.5 mmol) at 0° C. under nitrogen. The reactionmixture was allowed to warm up to room temperature and stirredovernight. The reaction mixture was then concentrated. To the residuewas added dichloromethane (80 ml), and the mixture was washed with HCl(0.1N, 30 ml), water, brine, dried over MgSO₄, and concentrated to givea brown solid (5.7 g).

ESI-MS calc. for C₁₅H₁₇NO₃: 259; Found: 282 (M+Na).

Intermediate 3

To a solution of Intermediate 2 (0.52 g, 2.0 mmol) in THF (10 ml) wasadded a solution of lithium hydroxide monohydrate (0.84 g, 20.0 mmol) inwater (10 ml). The reaction mixture was stirred at 80° C. overnight. Thesolvent was removed in vacuo and the aqueous residue was acidified byaddition of saturated sodium hydrogen sulfate solution and extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over MgSO_(4,) and concentrated to provide a brown solid(0.38 g).

ESI-MS: calc. for C₁₅H₁₉NO₄: 277; Found: 300 (M+Na).

Intermediate 4

To a solution of 1,2-dihydronaphthalene (4.0 g, 30.7 mmol) in ether (40ml) was added a solution of chlorosulfonyl isocyanate (2.7 ml, 31.0mmol) in ether (40 ml). After stirring at 0° C. for 0.5 hour, thereaction mixture was allowed to warm up to room temperature and allowedto stir for another 4 hours. The reaction mixture was poured into 20%aqueous sodium sulfite (80 ml) and stirred vigorously for one hour.After addition of ethyl acetate, the organic layer was separated and theaqueous phase was extracted with ethyl acetate. The combined organicextracts were washed with water and brine, dried over Na₂SO₄ andconcentrated to give a colorless oil (4.3 g) which was crystallized froma small amount of hexane (3 ml) to give the title compound as a whitesolid (3.0 g).

ESI-MS: calc. for C₁₁H₁₁NO: 173.1; Found: 174 (M+H), 196 (M+Na), 347(2M+1), 369 (2M+Na).

Intermediate 5

Intermediate 5 was prepared from Intermediate 4 in an analogous mannerto the one described for the preparation of Intermediate 2.

ESI-MS: calc. for C₁₆H₁₉NO₃: 273.1; Found: 296 (M+Na).

Intermediate 6

Intermediate 6 was prepared from Intermediate 5 in an analogous mannerto the one described for the preparation of Intermediate 3.

ESI-MS: calc. for C₁₆H₂₁NO₄: 291.2; Found: 314 (M+Na).

Intermediate 7

To a solution of tetralone (5.0 g, 34.2 mmol) in THF (75.0 ml) at −78°C. under nitrogen was added methyllithium (45.6 ml, 68.4 mmol). Thereaction mixture was stirred at −78° C. for four hours, and warmed up toroom temperature and allowed to stir overnight. The reaction mixture waspoured onto saturated aqueous ammonium chloride. The organic layer wasseparated, and the aqueous phase was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over MgSO₄ andevaporated to give a brown solid (5.4 g) which was used without furtherpurification for the preparation of Intermediate 8.

Intermediate 8

To Intermediate 7 (4.5 g, 27.8 mmol) in toluene (150 ml) was addedpyridinium p-toluenesulfonate (0.35 mg, 1.39 mmol). The reaction mixturewas refluxed by using a Dean-Stark trap for one hour and concentrated togive a brown oil (4.5 g) which was purified by column chromatography onsilica gel (25:1 hexane/ethyl acetate) to give a yellow oil (3.7 g).

Intermediate 9

To a solution of intermediate 8 (0.20 g, 1.388 mmol) in ether (5 ml) wasadded a solution of chlorosulfonyl isocyanate (0.36 ml, 4.16 mmol) inether (5 ml). After stirring at 0° C. for 24 hours, the reaction mixturewas quenched with water. The organic layer was separated and poured into20% aqueous sodium sulfite (3 ml). The pH was adjusted to 7-8 byaddition of 15% aqueous KOH. The resulting mixture was stirred at 0° C.for one hour and then at r.t. for four hours. The organic layer wasseparated and the aqueous phase was extracted with ether. The combinedorganic extracts were washed with water and brine, dried over Na₂SO₄,and concentrated to give the title compound as a yellow solid (80 mg).

ESI-MS: calc. for C₁₂H₁₃NO: 187.1; Found: 188 (M+H), 375 (2M+1), 397(2M+Na).

Intermediate 10

To a solution of Intermediate 9 (180 mg, 0.963 mmol) in THF (10 ml) at0° C. was added sodium hydride (77 mg, 1.924 mmol, 60% in mineral oil)and di-tert-butyl dicarbonate (314.9 mg, 1.44 mmol) under nitrogen.After stirring 10 min at 0° C., the ice water bath was removed and thereaction mixture was allowed to stir at r.t. for 5 hrs. The reactionmixture was quenched with 0.1 N HCl. The organic layer was separated andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄ and concentrated to give the title compoundas a yellow oil (400 mg).

ESI-MS: calc. for C₁₇H₂₁NO₃: 287; Found: 310 (M+Na).

Intermediate 11

To a solution of Intermediate 10 (0.33 g, 1.15 mmol) in THF (4 ml) wasadded a solution of sodium hydroxide (0.46 g, 11.5 mmol) in water (4ml). The reaction mixture was stirred at r.t. overnight. The solvent wasremoved in vacuo and the aqueous residue was acidified by addition ofsaturated aqueous sodium hydrogen sulfate and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover MgSO₄, and concentrated to provide a brown solid (0.33 g).

ESI-MS calc. for C₁₇H₂₃NO₄: 305; Found: 328 (M+Na).

Intermediate 12

To a solution of 1-benzosuberone (6.0 g, 37.5 mmol) in ethanol (100 ml)was added sodium borohydride (2.1 g, 56.2 mmol), and the reactionmixture was stirred at r.t. under nitrogen overnight. The reactionmixture was concentrated and diluted with ethyl acetate. The organiclayer was washed with water and brine, dried over MgSO₄ and evaporatedto give the title compound as a white solid (6.2 g).

Intermediate 13

To a solution of Intermediate 12 (6.2 g, 38.2 mmol) in toluene (150 ml)was added p-toluenesulfonic acid monohydrate (145 mg, 0.764 mmol). Thereaction mixture was refluxed by using a Dean-stark apparatus for 3 hrs,and solvent was removed to give the title compound as a brown oil (6.0g).

Intermediate 14

To a solution of Intermediate 13 (0.52 g, 3.57 mmol) in ether (10 ml)was added a solution of chlorosulfonyl isocyanate (0.93 ml, 10.7 mmol)in ether (10 ml). After stirring at 0° C. for 7 days, the reactionmixture was quenched with water. The organic layer was separated andpoured into 20% aqueous sodium sulfite (8 ml). The pH was adjusted to7-8 by addition of 15% aqueous KOH. The resulting mixture was stirred at0° C. for one hour and then at r.t. for four hours. The organic layerwas separated and the aqueous phase was extracted with ether. Thecombined organic extracts were washed with water and brine, dried overNa₂SO₄, and concentrated to give a white solid, which was recrystallizedfrom hexane and ether to give the title compound as a white solid (0.15g).

ESI-MS: calc. for C₁₂H₁₃NO: 187.1; Found: 188 (M+H), 375 (2M+1), 397(2M+Na).

Intermediate 15

Intermediate 15 was prepared from Intermediate 14 in an analogous mannerto the one described for the preparation of Intermediate 2.

ESI-MS: calc. for C₁₇H₂₁NO₃: 287; Found: 310 (M+Na).

Intermediate 16

Intermediate 16 was prepared from Intermediate 15 in an analogous mannerto the one described for the preparation of Intermediate 3.

ESI-MS calc. for C₁₇H₂₃NO₄: 305.2; Found: 328 (M+Na).

Intermediate 17

To a solution of 4-cyclohexyl4-formyl-N-(tertbutyloxycarbonyl)-piperidine (2.56 g, 8.68 mmol) intoluene (100 ml) was added acetic acid (2 ml) and1-amino-1-cyclopentanemethanol (1.0 g, 8.68 mmol). After refluxing byusing a Dean-Stark apparatus for 11 hours, the reaction mixture wasconcentrated. The residue was dissolved in acetic acid (70 ml) andhydrogenated overnight in the presence of platinum oxide (500 mg) undera balloon atmosphere of hydrogen gas. The catalyst was filtered off andsolvent was removed to give a colorless oil, which was dissolved inmethanol and made basic by addition of NaOH (5N, 4 ml) and concentrated.The residue was partitioned between water and CH₂Cl₂, the two layersseparated, and the aqueous layer extracted with CH₂Cl₂. The combinedorganic extracts were washed with brine, dried over MgSO₄ andconcentrated to give the title compound as a colorless oil (2.1 g).

ESI-MS: calc. for C₂₃H₄₂N₂O₃: 394.3; Found: 395 (M+1), 417 (M+Na).

Intermediate 18

To a solution of Intermediate 17 (2.1 g, 5.33 mmol) in CH₂Cl₂ (70 ml) at0° was added DMAP (0.65 g, 5.33 mmol), DIEA (3.76 ml, 21.3 mmol)followed by slow addition of phosgene (4.1 ml, 8.0 mmol). After stirringthe reaction mixture for one hour at 0° C., the ice-water bath wasremoved and the reaction mixture was continued to stir at r.t.overnight. The mixture was diluted with CH₂Cl₂, washed with water andbrine, dried over MgSO₄ and concentrated to give crude product, whichwas purified by column chromatography on silica gel (2% EtOAc/CH₂Cl₂ to5% EtOAc/CH₂Cl₂) to give the title compound as a white solid (1.2 g).

ESI-MS: calc. for C₂₄H₄₀N₂O₄: 420.3; Found: (M+1), (M+Na).

Intermediate 19

To the Intermediate 18 (1.2 g) was added hydrogen chloride (4.0 M indioxane). The reaction mixture was stirred at room temperature for 30minutes and the solvent was removed in vacuo to afford the titlecompound (1.2 g).

ESI-MS: calc. for C₁₉H₃₂N₂O₂: 320.3; Found: 321.1 (M+H).

Intermediate 20

To a solution of Intermediate 19 (1.2 g, 3.37 mmol) in dichloromethane(10 ml) was added 4-methylmorpholine (0.56 ml, 5.055 mmol), HOBt (0.5008mg, 3.71 mmol), EDC (0.97 g, 5.06 mmol), and Boc-D-4-chlorophenylalanine(1.1 g, 3.71 mmol). The reaction mixture was stirred at room temperaturefor 18 hrs. Water (3 ml) was added and solvent was removed in vacuo. Theaqueous phase was extracted with ethyl acetate. The combined organicextracts were washed with water, dried over MgSO₄, and concentrated toprovide a white solid (2.2 g), which was purified by columnchromatography on silica gel (7:1 CH₂Cl₂/EtOAc) to give a white solid(1.45 g).

ESI-MS: calc. for C₃₄H₄₉ClN₂O₅: 601; Found: 602 (M+H).

Intermediate 21

Intermediate 21 was prepared from Intermediate 20 in an analogous mannerto the one described for the preparation of Intermediate 19.

ESI-MS calc. for C₂₈H₄₀ClN₃O₃: 501; Found: 502 (M+H).

Intermediate 22

Intermediate 22 was prepared from (S)-(+)-2-amino-1-propanol in ananalogous manner to the one described for the preparation ofIntermediate 17.

ESI-MS: calc. for C₂₀H₃₈N₂O₃: 354; Found: 355 (M+H).

Intermediate 23

Intermediate 23 was prepared from Intermediate 22 in an analogous mannerto the one described for the preparation of Intermediate 18.

ESI-MS: calc. for C₂₁H₃₆N₂O₄: 380.3; Found: 381 (M+H).

Intermediate 24

Intermediate 24 was prepared from Intermediate 23 in an analogous mannerto the one described for the preparation of Intermediate 19.

ESI-MS: calc. for C₁₆H₂₈N₂O₂: 280.3; Found: 281 (M+H).

Intermediate 25

Intermediate 25 was prepared from Intermediate 24 in an analogous mannerto the one described for the preparation of Intermediate 20.

ESI-MS: calc. for C₃₀H₄₄ClN₃O₅: 561.3; Found: 562 (M+H).

Intermediate 26

Intermediate 26 was prepared from Intermediate 25 in an analogous mannerto the one described for the preparation of Intermediate 19.

ESI-MS: calc. for C₂₅H₃₆ClN₃O₃: 461.3; Found: 462 (M+H).

Intermediate 27

To a suspension of 1-aminocyclopropane-1-carboxylic acid (2.8 g, 27.7mmol) in THF (20 ml) was added borane-tetrahydrofuran complex (100 ml,100 mmol) slowly under nitrogen at r.t. The reaction mixture was stirredat 70° C. overnight, then cooled to 0° C. After addition of methanol(12.2 ml, 300 mmol), the mixture was allowed to stir for 30 minutes.Then acetic acid (1.6 ml, 27.7 mmol) was added. The reaction mixture wasconcentrated to provide the title compound as a colorless oil (3.0 g).

Intermediate 28

Intermediate 28 was prepared from Intermediate 27 in an analogous mannerto the one described for the preparation of Intermediate 17.

ESI-MS: calc. for C₂₁H₃₈N₂O₃: 366.3; Found: 367 (M+H).

Intermediate 29

To a solution of Intermediate 28 (0.8 g, 2.18 mmol) in CH₂Cl₂ (40 ml) at0° was added DMAP (0.266 g, 2.18 mmol), DIEA (1.52 ml, 8.74 mmol) andtriphosgene (0.648 g, 2.18 mmol). After stirring the reaction mixturefor one hour at 0° C., the ice-water bath was removed and the reactionmixture was allowed to stir at r.t. overnight. The mixture was dilutedwith CH₂Cl₂, washed with water and brine, dried over MgSO₄ andconcentrated to give crude product, which was purified by columnchromatography on silica gel (10% CH₂Cl₂/EtOAc) to give the titlecompound as a colorless oil (0.13 g).

ESI-MS: calc. for C₂₂H₃₆N₂O₄: 392; Found: 393 (M+1).

Intermediate 30

Intermediate 30 was prepared from Intermediate 29 in an analogous mannerto the one described for the preparation of Intermediate 19.

ESI-MS: calc. for C₁₇H₂₈N₂O₂: 292.2; Found: 293 (M+H).

Intermediate 31

Intermediate 31 was prepared from Intermediate 30 in an analogous mannerto the one described for the preparation of Intermediate 20.

ESI-MS: calc. for C₃₁H₄₄ClN₃O₅: 573.3; Found: 574 (M+H).

Intermediate 32

Intermediate 32 was prepared from Intermediate 31 in an analogous mannerto the one described for the preparation of Intermediate 19.

ESI-MS: calc. for C₂₆H₃₆ClN₃O₃: 473; Found: 474 (M+H).

Intermediate 33

To a solution of the alcohol (9.41 g, 31.6 mmol) in CH₂Cl₂ (100 ml) at0° C. containing molecular sieves (2 g) and 4-methylmorpholine N-oxide(4.449 g, 37.98 mmol) was added TPAP (1.12 g, 3.16 mmol). After stirringthe reaction mixture at 0° C. for 0.5 h, the reaction mixture was warmedto room temperature and stirred further for 5 hrs. The reaction mixturewas concentrated to half the volume, diluted with hexane (250 ml),filtered through a silica gel pad and concentrated to give pure titlecompound (9.4 g).

Intermediate 34

To a solution of the aldehyde (2 g, 6.7 mmol) in toluene (50 ml) wasadded acetic acid (500 μl). After stirring the reaction mixture atreflux temperature using Dean Stark apparatus for 8 hrs, the mixture wasconcentrated and dissolved in acetic acid (30 ml). To the mixture wasadded PtO₂ (500 mg) which was stirred under an atmosphere of H₂overnight. The rection mixture was flushed with nitrogen, filtered andconcentrated to give the title compound (2 g).

Intermediate 35

To a solution of the amino alcohol (4.96 g, 13.47 mmol) in CH₂Cl₂ at 0°C. containing DIEA (6.98 g, 53.9 mmol), DMAP (1.64 g, 13.47 mmol) wasadded slowly a toluene solution of phosgene (1.93M, 10.47 ml, 20.21mmol). After stirring the reaction mixture for 1 hr at 0° C., thetemperature was raised to room temperature and stirred further for 2hrs. The reaction mixture was diluted with CH₂Cl₂, washed with water,brine, dried and concentrated. The residue was purified by columnchromatography over silica gel (5% EtOAc/CH₂Cl₂) to give pure product(3.95 g).

Intermediate 36

To a solution of Intermediate 35 (3.95 g) in CH₂Cl₂ was added 5 ml of asaturated HCl solution of EtOAc. After stirring the reaction mixture for30 minutes at room temperature, the solvent was removed and the residuelyophilized from a benzene/methanol solution to afford the titlecompound (3.85 g).

Intermediate 37

To a solution of Boc-D-4-Cl-Phe (1.6 g, 5.5 mmol) in CH₂Cl₂ (30 ml) wasadded EDC (1.84 g, 9.6 mmol), HOBT (1.298 g, 9.6 mmol), NMM (1.67 g,16.5 mmol) and followed by the oxazolidinone intermediate (1.65 g, 5mmol). After stirring the reaction mixture overnight at roomtemperature, the mixture was diluted with CH₂Cl₂, washed with water,dilute HCl, aqueous NaHCO₃ and brine. The organic layer was dried,concentrated and purified by chromatography on silica gel (10%acetone/CH₂Cl₂) to give 2.55 g of pure product.

ESI-MS: calc. for C₃₁H₄₆ClN₃O₅: 575; Found: 576 (M+H).

Intermediate 38

To a solution of Intermediate 37 (2.55 g) in CH₂Cl₂ (8 ml) was added asaturated HCl solution of EtOAc (8 ml). After stirring the solution for0.5 hr at 23° C., the mixture was concentrated and lyophilized frombenzene/methanol to furnish the desired product (2.4 g).

ESI-MS: calc. for C₂₆H₃₈ClN₃O₃: 475; Found: 476 (M+H).

Intermediate 39

To a solution of Boc-D-4-F-Phe (1.55 g, 5.5 mmol) in CH₂Cl₂ (30 ml) wasadded EDC (1.84 g, 9.6 mmol), HOBT (1.29 g, 9.6 mmol), NMM (1.67 g, 16.5mmol) and the oxazolidinone intermediate (1.65 g, 5 mmol). Afterstirring the reaction mixture overnight at 23° C., the mixture wasdiluted with CH₂Cl₂, washed with water, dilute HCl and aqueous NaHCO₃.The organic layer was dried, concentrated and purified by chromatographyon silica gel (8% acetone/CH₂Cl₂) to give pure product (2.34 g).

ESI-MS: calc. for C₃₁H₄₆FIN₃O₅: 559; Found: 560 (M+H).

Intermediate 40

The title compound was prepared in an analogous fashion as Intermediate38.

The following Examples are provided to illustrate the invention and arenot to be construed as limiting the scope of the invention in anymanner.

EXAMPLE 1

Step A

To a stirred solution of 4-F-D-Phe-4-cyclohexyl-piperidine-4-carboxylicacid ethyl ester HCl salt (187 mg, 0.34 mmol), Intermediate 6 (100 mg,0.34 mmol), PyBrop (176 mg, 0.38 mmol) and DMAP (25 mg, 0.2 mmol) indichloromethane (2 mL) was added DIEA (133 mg, 1.0 mmol). The solutionwas stirred 16 hr, concentrated and chromatographed directly (SiO₂,19:1EtOAc/methanol) to provide 144 mg of the Boc-protected product.

ESI-MS: calc. for C₄₁H₅₇FN₄O₅: 704; Found 705 (M+H), 605 (M+H-Boc).

Step B

To a stirred solution of the Boc-protected intermediate from Step A (130mg, 0.18 mmol) was added HCl-EtOAc (5 mL). The reaction was stirred for5 minutes at 50° C. and the mixture concentrated. The residue waspurified by preparative HPLC (C18 column, 45% to 60% acetonitrilegradient over 10 min. Two product fractions were collected, and thesolvent was removed in vacuo to afford 118 mg of the diastereomer D1 asa white solid and 91 mg of the diastereomer D2 as a white solid.

ESI-MS: calc. for D1: C₃₄H₄₄FN₃O₄: 577; Found 578 (M+H), 601 (M+Na);

¹HNMR (CD₃OD; 500 MH): 5.098 (m, 1H); 4.576 (d, J=3 Hz, 1H); 4.513 (d,J=3 Hz, 1H); 0.285 (dt, J=4.4, 13.2 Hz, 1H).

ESI-MS: calc. for D2: C₃₄H₄₄FN₃O₄: 577; Found 578 (M+H), 601 (M+Na);

¹HNMR (CD₃OD; 500 MHz): 5.082 (m, 1H); 4.667 (d, J=3.6 Hz, 1H); 4.633(d, J=3.4 Hz, 1H); 0.394 (dt, J=4.4, 13.2 Hz, 1H).

EXAMPLE 2

Step A

To a solution of Intermediate 3 (86.5 mg, 0.312 mmol) in dichloromethane(10 ml) were added 4-methylmorpholine (0.047 ml, 0.425 mmol), HOBt (42.2mg, 0.312 mmol), EDC (81.6 mg, 0.425 mmol), and the t-butyl amideintermediate (159.3 mg, 0.284 mmol). The reaction mixture was stirred atroom temperature for 18 hrs. Water (3 ml) was added and solvent wasremoved in vacuo. The aqueous phase was extracted with ethyl acetate.The combined organic extracts were washed with water and brine, driedover MgSO₄ and concentrated to provide a yellow solid (210 mg), whichwas purified by preparative TLC to give a yellow solid (120 mg).

ESI-MS: calc. for C₄₀H₅₅ClN4O₅: 706.4; Found: 707 (M+H).

Step B

To the Boc-protected intermediate from Step A (120 mg) was added 4.0MHCl in dioxane (1 mL). The reaction mixture was stirred at roomtemperature for 30 minutes and the solvent was removed in vacuo toafford the title compound (120 mg).

ESI-MS: calc. for C₃₅H₄₇ClN₄O₃: 606.4; Found: 607.4 (M+H).

EXAMPLES 3-14

Examples 3-14 were prepared from the appropriate Boc-protectedIntermediate and 4-substituted-piperidinyl-phenylalanine intermediate inan analogous two-step sequence described for Examples 1 and 2.

The Boc-protected intermediates with their mass spectral datacorresponding to these Examples are listed in the Table below.

Found EX. X R R′ Calc. MW ESI-MS 3 F

C₃₈H₅₀FN₃O₆ 663 664 (M + 1) 4 Cl

″ C₃₈H₅₀ClN₃O₆ 679 680 (M + 1) 5 Cl

C₃₉H₅₂ClN₃O₆ 693 694 (M + 1) 6 F

″ C₃₉H₅₂FN₃O₆ 677 678 (M + 1) 7 Cl

″ C₄₁H₅₇ClN₄O₅ 720 721 (M + 1) 8 Cl

″ C₄₄H₅₉ClN₄O₆ 774 775 (M + 1) 9 Cl

″ C₄₁H₅₅ClN₄O₆ 734 735 (M + 1) 10 Cl

″ C₄₂H₅₅ClN₄O₆ 746 747 (M + 1) 11 Cl

C₄₃H₅₉ClN₄O₆ 762 763 (M + 1) 12 Cl

″ C₄₀H₅₄ClN₃O₆ 707 708 (M + 1) 13 Cl

″ C₄₂H₅₉ClN₄O₅ 734 735 (M + 1) 14 Cl ″

C₄₂H₅₉ClN₄O₅ 734 735 (M + 1)

The final products after cleavage of the Boc-protecting group are listedin the Table below.

Found EX. X R R′ Calc. MW ESI-MS 3 F

C₃₃H₄₂FN₃O₄ 563 564 (M + 1) 4 Cl

″ C₃₃H₄₂ClN₃O₄ 579 580 (M + 1) 5 Cl

C₃₄H₄₄ClN₃O₄ 593 594 (M + 1) 6 F

″ C₃₄H₄₄FN₃O₄ 577 578 (M + 1) 7 Cl

″ C₃₆H₄₉ClN₄O₃ 620 621 (M + 1) 8 Cl

″ C₃₉H₅₁ClN₄O₄ 674 675 (M + 1) 9 Cl

″ C₃₆H₄₇ClN₄O₄ 634 635 (M + 1) 10 Cl

″ C₃₇H₄₇ClN₄O₄ 646 647 (M + 1) 11 Cl

C₃₈H₅₁ClN₄O₄ 662 663 (M + 1) 12 Cl

″ C₃₅H₄₆ClN₃O₄ 607 608 (M + 1) 13 Cl

″ C₃₇H₅₁ClN₄O₃ 634 635 (M + 1)

EXAMPLE 14

To the Boc-protected intermediate from the Table above (30 mg) was added4.0M HCl in dioxane (1 mL) at 0° C., and the reaction mixture wasstirred at room temperature for 20 minutes and the solvent was removedin vacuo to give a yellow oil, which was purified by preparative HPLC toafford the title compound (4 mg).

ESI-MS: calc. for C₃₇H51ClN₄O₃: 634; Found: 635(M+H.

EXAMPLE 15

Step A

A 25-mL, 2-neck round-bottomed flask was purged under nitrogen andcharged with 1,4-dihydro-1,4-methanonaphthalene (2-1) (0.8365 g, 5.88mmol). Chlorosulfonyl isocyanate (1.02 mL, 11.76 mmol) was addeddropwise and then stirred at r.t. under N₂ for 3 days. The mixture waspoured into 60 mL of 20% aq. Na₂SO₃ solution and stirred vigorously for1 h. Ethyl acetate was added, the layers separated and the aqueous layerextracted by ethyl acetate. The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give a redoil. Purification by chromatography on silica gel (9:1 methylenechloride-acetone) gave 2-2 as a white solid (0.452 g).

ESI-MS: Calcd for C₁₂H₁₁NO: 185.08; Found: 186 (MW+1).

Step B

To a solution of compound 2-2 (0.449 g, 2.425 mmol) in 12 mL ofmethylene chloride at 0° C. under nitrogen, TEA (1.01 mL, 7.275 mmol),(Boc)₂O (0.582 g, 2.667 mmol), and DMAP (0.03 g, 0.243 mmol) were added.The reaction mixture was warmed to r.t. and stirred overnight. Thereaction mixture was diluted with methylene chloride and washed with 1NHCl and brine, dried over MgSO₄, filtered and concentrated. Purificationby chromatography on silica gel (30:1 methylene chloride-acetone) gavecompound 2-3 as an off-white solid (0.6694 g).

ESI-MS: Calcd. for C₁₇H₁₉NO₃: 285.14; Found: 308 (M⁺+Na).

Step C

To a solution of compound 2-3 (0.6658 g, 2.33 mmol) in 50 mL of THF,lithium hydroxide (4.47 g) in 50 mL of H₂O was added. The reactionmixture was refluxed at 75° C. overnight. The reaction mixture wasconcentrated and H₂O was added and then acidified by adding aqueousNaHSO₄ solution until pH=2 was achieved. The solution was extracted withEtOAc and the combined organic extracts were washed with brine, driedover MgSO₄, filtered, and concentrated to give compound 24 as anoff-white solid (0.6396 g).

ESI-MS: Calcd. for C₁₇H₂₁NO₄: 303.15; Found: 304 (M⁺+1).

Step D

Acid 2-4 (0.043 g, 0.143 mmol) was dissolved in 0.65 mL of methylenechloride, and then the 4-F-D-Phe-4-cyclohexyl-piperidine-4-carboxylicacid tert-butyl amide intermediate in Scheme 2 (0.056 g, 0.13 mmol),DIEA (0.09 mL, 0.52 mmol), EDC (0.027 g, 0.143 mmol), and HOBt (0.019 g,0.143 mmol) were added. The resulting mixture was stirred at r.t.overnight, and then diluted with methylene chloride, and washed with 1NHCl solution, saturated NaHCO₃ solution, and brine. The organic layerwas dried over MgSO₄, filtered, and concentrated. The crude product waspurified by column chromatography on silica gel (30:1 to 9:1 methylenechloride-acetone) to give 2-5 as a white foamy solid (0.0643 g).

ESI-MS: Calcd. for C₄₂H₅₇N₄O₅F: 716.43; Found: 717 (M⁺+1).

Step E

Compound 2-5 (0.0615 g, 0.086 mmol) was dissolved in 0.21 mL ofmethylene chloride and 0.21 mL of trifluoroacetic acid. This solutionwas stirred at r.t. for 30 min, and then coevaporated with toluene (2×5mL) and diethyl ether (2×5 mL) to give 2-6 as a white foamy solid (0.062g).

ESI-MS: Calcd. for C₃₇H₄₉N₄O₃F: 616.38; Found: 617 (M⁺+1).

EXAMPLES 16-28

Examples 16-28 were prepared from the Boc-protected amino acid 2-4 andappropriate 4-substituted-piperidinyl-phenylalanine intermediate asdepicted in Scheme 2 for Example 15. The Boc-protecting group wascleaved with trifluoroacetic acid in the usual fashion to afford thefinal product. The Examples are listed in the Table below along withtheir mass spectral characterization data.

EX. Y X R⁶ Exact Mass Mass Spec. 16

Cl d₁ + d₂ 632.25 633 (M⁺ + 1) 17

F d₁ + d₂ 616.38 617 (M⁺ + 1) 18

F d₁ + d₂ 644.37 645 (M⁺ + 1) 19

Cl d₁ + d₂ 621.32 622 (M⁺ + 1) 20

Cl d₁ + d₂ 637.31 638 (M⁺ + 1) 21

Cl d₁ + d₂ 653.31 654 (M⁺ + 1) 22

Cl d₁ + d₂ 615.27 616 (M⁺ + 1) 23

Cl d₁ + d₂ 631.26 632 (M⁺ + 1) 24

Cl d₁ + d₂ 647.26 648 (M⁺ + 1) 25

Cl d₁ 647.26 648 (M⁺ + 1) 26

Cl d₁ + d₂ 603.31 604 (M⁺ + 1) 27

Cl d₁ 603.31 604 (M⁺ + 1) 28

Cl d₂ 603.31 604 (M⁺ + 1)

Biological Assays

A. Binding Assay

The membrane binding assay was used to identify competitive inhibitorsof ¹²⁵I-NDP-alpha-MSH binding to cloned human MCRs expressed in L- orCHO-cells.

Cell lines expressing melanocortin receptors were grown in T-180 flaskscontaining selective medium of the composition: 1 L Dulbecco's modifiedEagles Medium (DMEM) with 4.5 g L-glucose, 25 mM Hepes, without sodiumpyruvate, (Gibco/BRl); 100 ml 10% heat-inactivated fetal bovine serum(Sigma); 10 ml 10,000 unit/ml penicillin & 10,000 ug/ml streptomycin(Gibco/BRl); 10 ml 200 mM L-glutamine (Gibco/BRl); 1 mg/ml Geneticin(G418) (Gibco/BRl). The cells were grown at 37° C. with CO₂ and humiditycontrol until the desired cell density and cell number was obtained.

The medium was poured off and 10 mls/monolayer of enzyme-freedissociation media (Specialty Media Inc.) was added. The cells wereincubated at 37° C. for 10 minutes or until cells sloughed off whenflask was banged against hand.

The cells were harvested into 200 ml centrifuge tubes and spun at 1000rpm, 4° C., for 10 min. The supernatant was discarded and the cells wereresuspended in 5 mls/monolayer membrane preparation buffer having thecomposition: 10 mM Tris pH 7.2-7.4; 4 ug/ml Leupeptin (Sigma); 10 uMPhosphoramidon (Boehringer Mannheim); 40 ug/ml Bacitracin (Sigma); 5ug/ml Aprotinin (Sigma); 10 mM Pefabloc (Boehringer Mannheim). The cellswere homogenized with motor-driven dounce (Talboy setting 40), using 10strokes and the homogenate centrifuged at 6,000 rpm, 4° C., for 15minutes.

The pellets were resuspended in 0.2 mls/monolayer membrane prep bufferand aliquots were placed in tubes (500-1000 ul/tube) and quick frozen inliquid nitrogen and then stored at −80° C.

Test compounds or unlabelled NDP-α-MSH was added to 100 μL of membranebinding buffer to a final concentration of 1 μM. The membrane bindingbuffer had the composition: 50 mM Tris pH 7.2; 2 mM CaCl2; 1 mM MgCl2; 5mM KCl; 0.2% BSA; 4 ug/ml Leupeptin (SIGMA); 10 uM Phosphorarnidon(Boehringer Mannheim); 40 ug/ml Bacitracin (SIGMA); 5 ug/ml Aprotinin(SIGMA); and 10 mM Pefabloc (Boehringer Mannheim). One hundred μl ofmembrane binding buffer containing 10-40 ug membrane protein was added,followed by 100 μM 125I-NDP-α-MSH to final concentration of 100 pM. Theresulting mixture was vortexed briefly and incubated for 90-120 min atroom temp while shaking.

The mixture was filtered with Packard Microplate 196 filter apparatususing Packard Unifilter 96-well GF/C filter with 0.1% polyethyleneimine(Sigma). The filter was washed (5 times with a total of 10 ml per well)with room temperature of filter wash having the composition: 50 mMTris-HCl pH 7.2 and 20 mM NaCl. The filter was dried, and the bottomsealed and 50 ul of Packard Microscint-20 was added to each well. Thetop was sealed and the radioactivity quantitated in a Packard TopcountMicroplate Scintillation counter.

B. Functional Assay

Functional cell based assays were developed to discriminate melanocortinreceptor agonists from antagonists.

Cells (for example, CHO- or L-cells or other eukaryotic cells)expressing a human melanocortin receptor (see e.g. Yang-Y K; Ollmann-MM; Wilson-B D; Dickinson-C; Yamada-T; Barsh-G S; Gantz-I;Mol-Endocrinol. 1997 March; 11(3): 274-80) were dissociated from tissueculture flasks by rinsing with Ca and Mg free phosphate buffered saline(14190-136, Life Technologies, Gaithersburg, Md.) and detached following5 minutes incubation at 37° C. with enzyme free dissociation buffer(S-014B, Specialty Media, Lavellette, N.J.). Cells were collected bycentrifugation and resuspended in Earle's Balanced Salt Solution(14015-069, Life Technologies, Gaithersburg, Md.) with additions of 10mM HEPES pH 7.5, 5 mM MgCl₂, 1 mM glutamine and 1 mg/ml bovine serumalbumin. Cells were counted and diluted to 1 to 5×10⁶/ml. Thephosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was added tocells to 0.6 mM.

Test compounds were diluted in dimethylsulfoxide (DMSO) (10⁻⁵ to 10⁻¹⁰M) and 0.1 volume of compound solution was added to 0.9 volumes of cellsuspension; the final DMSO concentration was 1%. After room temperatureincubation for 45 min., cells were lysed by incubation at 100° C. for 5min. to release accumulated cAMP.

cAMP was measured in an aliquot of the cell lysate with the Amersham(Arlington Heights, Ill.) cAMP detection assay (RPA556). The amount ofcAMP production which resulted from an unknown compound was compared tothat amount of cAMP produced in response to alpha-MSH which was definedas a 100% agonist. The EC₅₀ is defined as the compound concentrationwhich results in half maximal stimulation, when compared to its ownmaximal level of stimulation.

Antagonist Assay

Antagonist activity was defined as the ability of a compound to blockcAMP production in response to alpha-MSH. Solution of test compounds andsuspension of receptor containing cells were prepared and mixed asdescribed above; the mixture was incubated for 15 min., and an EC₅₀ dose(approximately 10 nM alpha-MSH) was added to the cells. The assay wasterminated at 45 min. and cAMP quantitated as above. Percent inhibitionwas determined by comparing the amount of cAMP produced in the presenceto that produced in the absence of test compound.

C. In vivo Food Intake Models

1) Overnight Food Intake

Sprague Dawley rats are injected intracerebroventricularly with a testcompound in 400 nL of 50% propylene glycol/artificial cerebrospinalfluid one hour prior to onset of dark cycle (12 hours). Food intake isdetermined using a computerized system in which each rat's food isplaced on a computer monitored balance. Cumulative food intake for 16hours post compound administration is measured.

2) Food Intake in Diet Induced Obese Mice

Male C57/B16J mice maintained on a high fat diet (60% fat calories) for6.5 months from 4 weeks of age are are dosed intraperitoneally with testcompound. Food intake and body weight are measured over an eight dayperiod. Biochemical parameters relating to obesity, including leptin,insulin, triglyceride, free fatty acid, cholesterol and serum glucoselevels are determined.

D. Rat Ex Copula Assay

Sexually mature male Caesarian Derived Sprague Dawley (CD) rats (over 60days old) are used with the suspensory ligament surgically removed toprevent retraction of the penis back into the penile sheath during theex copula evaluations. Animals receive food and water ad lib and arekept on a normal light/dark cycle. Studies are conducted during thelight cycle.

1) Conditioning to Supine Restraint for Ex Copula Reflex Tests

This conditioning takes ˜4 days. Day 1, the animals are placed in adarkened restrainer and left for 15-30 minutes. Day 2, the animals arerestrained in a supine position in the restrainer for 15-30 minutes. Day3, the animals are restrained in the supine position with the penilesheath retracted for 15-30 minutes. Day 4, the animals are restrained inthe supine position with the penile sheath retracted until penileresponses are observed. Some animals require additional days ofconditioning before they are completely acclimated to the procedures;non-responders are removed from further evaluation. After any handlingor evaluation animals are given a treat to ensure positivereinforcement.

2) Ex Copula Reflex Tests

Rats are gently restrained in a supine position with their anteriortorso placed inside a cylinder of adequate size to allow for normal headand paw grooming. For a 400-500 gram rat, the diameter of the cylinderis approximately 8 cm. The lower torso and hind limbs are restrainedwith a non-adhesive material (vetrap). An additional piece of vetrapwith a hole in it, through which the glans penis will be passed, isfastened over the animal to maintain the preputial sheath in a retractedposition. Penile responses will be observed, typically termed ex copulagenital reflex tests. Typically, a series of penile erections will occurspontaneously within a few minutes after sheath retraction. The types ofnormal reflexogenic erectile responses include elongation, engorgement,cup and flip. An elongation is classified as an extension of the penilebody. Engorgement is a dilation of the glans penis. A cup is defined asan intense erection where the distal margin of the glans penismomentarily flares open to form a cup. A flip is a dorsiflexion of thepenile body.

Baseline and or vehicle evaluations are conducted to determine how andif an animal will respond. Some animals have a long duration until thefirst response while others are non-responders altogether. During thisbaseline evaluation latency to first response, number and type ofresponses are recorded. The testing time frame is 15 minutes after thefirst response.

After a minimum of 1 day between evaluations, these same animals areadministered the test compound at 20 mg/kg and evaluated for penilereflexes. All evaluations are videotaped and scored later. Data arecollected and analyzed using paired 2 tailed t-tests to comparedbaseline and/or vehicle evaluations to drug treated evaluations forindividual animals. Groups of a minimum of 4 animals are utilized toreduce variability.

Positive reference controls are included in each study to assure thevalidity of the study. Animals can be dosed by a number of routes ofadministration depending on the nature of the study to be performed. Theroutes of administration includes intravenous (IV), intraperitoneal(IP), subcutaneous (SC) and intracerebral ventricular (ICV).

E. Models of Female Sexual Dysfunction

Rodent assays relevant to female sexual receptivity include thebehavioral model of lordosis and direct observations of copulatoryactivity. There is also a urethrogenital reflex model in anesthetizedspinally transected rats for measuring orgasm in both male and femalerats. These and other established animal models of female sexualdysfunction are described in McKenna K E et al, A Model For The Study ofSexual Function In Anesthetized Male And Female Rats, Am. J. Physiol.(Regulatory Integrative Comp. Physiol 30): R1276-R1285, 1991; McKenna KE et al, Modulation By Peripheral Serotonin of The Threshold For SexualReflexes In Female Rats, Pharm. Bioch. Behav., 40:151-156, 1991; andTakahashi L K et al, Dual Estradiol Action In The Diencephalon And TheRegulation Of Sociosexual Behavior In Female Golden Hamsters, BrainRes., 359:194-207, 1985.

Representative compounds of the present invention were tested and foundto bind to the melanocortin-4 receptor. These compounds were generallyfound to have IC₅₀ values less than 2 μM. Representative compounds ofthe present invention were also tested in the functional assay and foundgenerally to activate the melanocortin-4 receptor with EC₅₀ values lessthan 1 μM.

EXAMPLES OF A PHARMACEUTICAL COMPOSITION

As a specific embodiment of an oral composition of a composition of thepresent invention, 5 mg of Example 2 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

As another specific embodiment of an oral composition of a compound ofthe present invention, 2.5 mg of Example 2 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound of structural formula I:

wherein Q is

Cy is selected from the group consisting of aryl, 5- or 6-memberedheteroaryl, 5- or 6-membered heterocyclyl, and 5- to 7-memberedcarbocyclyl; wherein Cy is substituted with one to three groupsindependently selected from R³; A is O, S(O)_(m), NR⁷, or CH₂; m is 0,1, or 2; n is 0, 1, 2, or 3; p is 0, 1 or 2; q is 0, 1 or 2; r is 1, 2,or 3; R¹ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,(CHR⁷)_(n)—C₃₋₇ cycloalkyl, (CHR⁷)_(n)aryl, and (CHR⁷)_(n)heteroaryl; inwhich aryl and heteroaryl are unsubstituted or substituted with one tothree groups independently selected from R⁶; and alkyl and cycloalkylare unsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; R² is selected from the group consisting ofhydrogen, C₁₋₈ alkyl, (CH₂)_(n)C₃₋₇ cycloalkyl, and (CH₂)_(n)-aryl; eachR³ is independently selected from hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-aryl,(CH₂)_(n)C₃₋₇ cycloalkyl, (CH₂)_(n)-heteroaryl, halo, OR⁷, NHSO₂R⁷,N(R⁷)₂, C≡N, CO₂R⁷, C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO₂N(R⁷)₂, S(O)_(m)R⁷, CF₃,and OCF₃; R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₃₋₈ cycloalkyl; or R⁴ and R⁵together with the nitrogen to which they are attached form a 5- to8-membered ring optionally containing an additional heteroatom selectedfrom O, S, and NR⁷; wherein alkyl and cycloalkyl are unsubstituted orsubstituted with one to three groups independently selected from R⁶ andoxo; R⁶ is selected from the group consisting of  C₁₋₈ alkyl, (CH₂)_(n)-aryl,  (CH₂)_(n)C₃₋₇ cycloalkyl,  (CH₂)_(n)-heteroaryl, halo,  OR⁷,  NHSO₂R⁷,  N(R⁷)₂,  C≡N,  CO₂R⁷,  C(R⁷)(R⁷)N(R⁷)₂,  NO₂, SO₂N(R⁷)₂,  S(O)_(m)R⁷,  CF₃, and  OCF₃; each R⁷ is independentlyselected from the group consisting of hydrogen, C₁₋₈ alkyl,(CH₂)_(n)-aryl, and (CH₂)_(n)C₃₋₇ cycloalkyl; each R⁸ is independentlyselected from the group consisting of hydrogen, C₁₋₈ alkyl,(CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl;wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups independently selected from R⁶; and alkyl, cycloalkyl, and(CH₂)_(n) are unsubstituted or substituted with one to three groupsindependently selected from R⁶ and oxo; or two R⁸ groups together withthe atoms to which they are attached form a 5- to 8-membered mono- orbi-cyclic ring system optionally containing an additional heteroatomselected from O, S, and NR⁷; R⁹ is hydrogen or C₁₋₄ alkyl; X is selectedfrom the group consisting of C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl,(CH₂)_(n)aryl, (CH₂)_(n)heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N,(CH₂)_(n)CON(R⁸R⁸), (CH₂)_(n)CO₂R⁸, (CH₂)_(n)COR⁸ (CH₂)_(n)NR⁸C(O)R⁸,(CH₂)_(n)NR⁸CO₂R⁸, (CH₂)_(n)NR⁸C(O)N(R⁸)₂, (CH₂)_(n)NR⁸SO₂R⁸,(CH₂)_(n)S(O)_(m)R⁸, (CH₂)_(n)SO₂N(R⁸)(R⁸), (CH₂)_(n)OR⁸,(CH₂)_(n)OC(O)R⁸, (CH₂)_(n)OC(O)OR⁸, (CH₂)_(n)OC(O)N(R⁸)₂,(CH₂)_(n)N(R⁸)(R⁸), and (CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸); wherein aryl andheteroaryl are unsubstituted or substituted with one to three groupsselected from R⁶, and alkyl, (CH₂)_(n), cycloalkyl, and heterocyclyl areunsubstituted or substituted with one to four groups independentlyselected from R⁶ and oxo; Y is selected from the group consisting ofhydrogen, C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)aryl,(CH₂)_(n)heterocyclyl, and (CH₂)_(n)heteroaryl; wherein aryl andheteroaryl are unsubstituted or substituted with one to three groupsselected from R⁶; and alkyl, (CH₂)_(n), cycloalkyl, and heterocyclyl areoptionally substituted with one to three groups selected from R⁶ andoxo; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1 wherein Cy is selected from the group consisting of benzene,pyridine, pyrazine, piperidine, and cyclohexane.
 3. The compound ofclaim 2 wherein Cy is benzene or cyclohexane.
 4. The compound of claim 1wherein R¹ is CH(R⁷)-aryl or CH(R⁷)-heteroaryl wherein aryl andheteroaryl are optionally substituted with one or two R⁶ groups.
 5. Thecompound of claim 4 wherein R¹ is benzyl optionally substituted with oneor two groups selected from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, andOCF₃.
 6. The compound of claim 5 wherein R¹ is 4-chlorobenzyl,4-fluorobenzyl, or 4-methoxybenzyl.
 7. The compound of claim 1 whereinR² is H or CH₃.
 8. The compound of claim 1 wherein X is (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C(O)N(R⁸)(R⁸),(CH₂)_(n)CO₂R⁸, (CH₂)_(n)OR⁸, (CH₂)_(n)NR⁸C(O)R⁸, or (CH₂)_(n)NR⁸SO₂R⁸,wherein aryl and heteroaryl are optionally substituted with one to threegroups selected from R⁶; heterocyclyl is optionally substituted with oneto three groups selected from R⁶ and oxo; and the (CH₂)_(n) group isoptionally substituted with one to three groups selected from R⁷, halo,S(O)_(m)R⁷, N(R⁷)₂, and OR⁷.
 9. The compound of claim 8 wherein X isCH₂-heteroaryl, CH₂-heterocyclyl, NHC(O)R⁸, CO₂R⁸, or C(O)N(R⁸)(R⁸),wherein heteroaryl is optionally substituted with one to three groupsselected from R⁶; heterocyclyl is optionally substituted with one tothree groups selected from R⁶ and oxo; and wherein R⁸ is eachindependently selected from H and C₁₋₆ alkyl optionally substituted withOR⁷, SR⁷, or N(R⁷)₂, or 2 R⁷ groups together with the nitrogen to whichthey are attached form a 5- or 6-membered ring optionally having anadditional heteroatom selected from O, S and NR⁷.
 10. The compound ofclaim 9 wherein heteroaryl is selected from the group consisting ofpyridyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl,oxadiazolyl, pyrazolyl, and imidazolyl.
 11. The compound of claim 1wherein Y is C₁₋₈ alkyl, (CH₂)_(n)C₅₋₇ cycloalkyl, (CH₂)_(n)-aryl,(CH₂)_(n)-heterocyclyl or (CH₂)_(n)-heteroaryl, wherein aryl andheteroaryl are optionally substituted with one to three groups selectedfrom R⁶; and (CH₂)_(n), alkyl, cycloalkyl, and heterocyclyl areoptionally substituted with one to three groups selected from R⁶ andoxo.
 12. The compound of claim 11 wherein Y is cyclohexyl, cycloheptyl,cyclopentyl, phenyl, or C₁₋₆ alkyl, unsubstituted or substituted withone to three groups selected from R⁶ and oxo.
 13. The compound of claim12 wherein Y is cyclohexyl or C₁₋₆ alkyl, wherein the cyclohexyl andalkyl groups are unsubstituted or substituted with one to three groupsselected from R⁶ and oxo.
 14. The compound of claim 1 of formula Ia:

wherein Cy is phenyl or cyclohexyl, wherein Cy is substituted with oneto three groups independently selected from R³; n is 1 or 2; p is 0, 1,or 2; R² is selected from the group consisting of hydrogen, C₁₋₆ alkyl,and C₅₋₆ cycloalkyl; each R³ is independently selected from hydrogen,C₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)C₃₋₇ cycloalkyl,(CH₂)_(n)-heteroaryl, halo, OR⁷, NHSO₂R⁷, N(R⁷)₂, N≡N CO₂R⁷,C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO₂N(R⁷)₂, S(O)_(m)R⁷, CF₃, and OCF₃; R⁴ and R⁵are each independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, and C₅₋₆ cycloalkyl; or R⁴ and R⁵ together with the nitrogento which they are attached form a 5- to 8-membered ring optionallycontaining an additional heteroatom selected from O, S, and NR⁷; whereinalkyl and cycloalkyl are unsubstituted or substituted with one to threegroups independently selected from R⁶ and oxo; R⁶ is selected from thegroup consisting of C₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)C₃₋₇cycloalkyl,(CH₂)_(n)-heteroaryl, halo, OR⁷, NHSO₂R⁷, N(R⁷)₂, C≡N, CO₂R⁷,C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO₂N(R⁷)₂, S(O)_(m)R⁷, CF₃, and OCF₃; each R⁷ isindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, and C₃₋₆ cycloalkyl; each R⁸ is independently selected from thegroup consisting of hydrogen, C₁₋₅ alkyl, aryl, heteroaryl, and C₅₋₆cycloalkyl; wherein aryl and heteroaryl are unsubstituted or substitutedwith one to three groups independently selected from R⁶; and alkyl andcycloalkyl are unsubstituted or substituted with one to three groupsindependently selected from R⁶ and oxo; or two R⁸ groups together withthe atoms to which they are attached form a 5- to 8-membered mono- orbi-cyclic ring optionally containing an additional heteroatom selectedfrom O, S, and NR⁷; R⁹ is hydrogen or C₁₋₄ alkyl; X is selected from thegroup consisting of C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈cycloalkyl, (CH₂)_(n)aryl,(CH₂)_(n)heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N,(CH₂)_(n)CON(R⁸R⁸), (CH₂)_(n)CO₂R⁸, (CH₂)_(n)COR⁸ (CH₂)_(n)NR⁸C(O)R⁸,(CH₂)_(n)NR⁸CO₂R⁸, (CH₂)_(n)NR⁸C(O)N(R⁸)₂, (CH₂)_(n)NR⁸SO₂R⁸,(CH₂)_(n)S(O)mR⁸, (CH₂)_(n)SO₂N(R⁸)(R⁸), (CH₂)_(n)OR⁸, (CH₂)_(n)OC(O)R⁸,(CH₂)_(n)OC(O)OR⁸, (CH₂)_(n)OC(O)N(R⁸)₂, (CH₂)_(n)N(R⁸)(R⁸), and(CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸); wherein aryl and heteroaryl are unsubstitutedor substituted with one to three groups selected from R⁶, and alkyl,(CH₂)_(n), cycloalkyl, and heterocyclyl are unsubstituted or substitutedwith one to four groups independently selected from R⁶ and oxo; Y isselected from the group consisting of hydrogen, C₁₋₈ alkyl,(CH₂)_(n)C₃₋₆ cycloalkyl, (CH₂)_(n)aryl, and (CH₂)_(n)heteroaryl;wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), and cycloalkyl areunsubstituted or substituted with one to three groups selected from R⁶and oxo; or a pharmaceutically acceptable salt thereof.
 15. The compoundof claim 14 wherein the carbon atom marked with * has the Rconfiguration.
 16. The compound of claim 14 wherein X is selected fromthe group consisting of:


17. The compound of claim 16 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1 of formula Ib:

wherein Cy is phenyl or cyclohexyl, wherein Cy is substituted with oneto three groups independently selected from R³; n is 1 or 2; R² isselected from the group consisting of hydrogen, C₁₋₆ alkyl, and C₅₋₆cycloalkyl; each R³ is independently selected from hydrogen, C₁₋₈ alkyl,(CH₂)_(n)-aryl, (CH₂)_(n)C₃₋₇ cycloalkyl, (CH₂)_(n)-heteroaryl, halo,OR⁷, NHSO₂R⁷, N(R⁷)₂, C≡N CO₂R⁷, C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO₂N(R⁷)₂,S(O)_(m)R⁷, CF₃, and OCF₃; R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, and C₅₋₆ cycloalkyl;or R⁴ and R⁵ together with the nitrogen to which they are attached forma 5- to 8-membered ring optionally containing an additional heteroatomselected from O, S, and NR⁷; wherein alkyl and cycloalkyl areunsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; R⁶ is selected from the group consisting ofC₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)C₃₋₇cycloalkyl,(CH₂)_(n)-heteroaryl, halo, OR⁷, NHSO₂R⁷, N(R⁷)₂, C≡N, CO₂R⁷,C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO₂N(R⁷)₂, S(O)_(m)R⁷, CF₃and OCF₃; each R⁷ isindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, and C₃₋₆ cycloalkyl; each R⁸ is independently selected from thegroup consisting of hydrogen, C₁₋₅ alkyl, aryl, heteroaryl, and C₅₋₆cycloalkyl; wherein aryl and heteroaryl are unsubstituted or substitutedwith one to three groups independently selected from R⁶; and alkyl andcycloallkyl are unsubstituted or substituted with one to three groupsindependently selected from R⁶ and oxo; or two R⁸ groups together withthe atoms to which they are attached form a 5- to 8-membered mono- orbi-cyclic ring optionally containing an additional heteroatom selectedfrom O, S, and NR⁷; R⁹ is hydrogen or C₁₋₄ alkyl; X is selected from thegroup consisting of C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈cycloalkyl, (CH₂)_(n)aryl,(CH₂)_(n)heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N,(CH₂)_(n)CON(R⁸R⁸), (CH₂)_(n)CO₂R⁸, (CH₂)_(n)COR⁸ (CH₂)_(n)NR⁸C(O)R⁸,(CH₂)_(n)NR⁸CO₂R⁸, (CH₂)_(n)NR⁸C(O)N(R⁸)₂, (CH₂)_(n)NR⁸SO₂R⁸,(CH₂)_(n)S(O)mR⁸, (CH₂)_(n)SO₂N(R⁸)(R⁸), (CH₂)_(n)OR⁸, (CH₂)_(n)OC(O)R⁸,(CH₂)_(n)OC(O)OR⁸, (CH₂)_(n)OC(O)N(R⁸)₂, (CH₂)_(n)N(R⁸)(R⁸), and(CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸); wherein aryl and heteroaryl are unsubstitutedor substituted with one to three groups selected from R⁶; and alkyl,(CH₂)_(n), cycloalkyl, and heterocyclyl are unsubstituted or substitutedwith one to four groups independently selected from R⁶ and oxo; Y isselected from the group consisting of hydrogen, C₁₋₈ alkyl,(CH₂)_(n)C₃₋₆ cycloalkyl, (CH₂)_(n)aryl, and (CH₂)_(n)heteroaryl;wherein aryl and heteroaryl are unsubstituted or substituted with one tothree groups selected from R⁶; and alkyl, (CH₂)_(n), and cycloalkyl areunsubstituted or substituted with one to three groups selected from R⁶and oxo; or a pharmaceutically acceptable salt thereof.
 19. The compoundof claim 18 wherein the carbon atom marked with * has the Rconfiguration.
 20. The compound of claim 18 wherein X is selected fromthe group consisting of:


21. The compound of claim 20 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 22. A method for thetreatment or prevention of disorders, diseases or conditions responsiveto the activation of the melanocortin-4 receptor in a subject in needthereof which comprises administering to the subject a therapeuticallyor prophylactically effective amount of a compound according to claim 1.23. A method for the treatment of obesity in a subject in need thereofwhich comprises administering to the subject a therapeutically effectiveamount of a compound according to claim
 1. 24. A method for thetreatment of diabetes mellitus in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound according to claim
 1. 25. A method for the treatment of male orfemale sexual dysfunction in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound according to claim
 1. 26. A method for the treatment oferectile dysfunction in a subject in need thereof comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound according to claim
 1. 27. Apharmaceutical composition which comprises a compound of claim 1 and apharmaceutically acceptable carrier.
 28. A pharmaceutical composition ofclaim 27 further comprising a second active ingredient selected from thegroup consisting of an insulin sensitizer, an insulin mimetic, asulfonylurea, an α-glucosidase inhibitor, an HMG-CoA reductaseinhibitor, a sequestrant cholesterol lowering agent, a β3 adrenergicreceptor agonist, a neuropeptide Y antagonist, a type Vcyclic-GMP-selective phosphodiesterase inhibitor, an α₂-adrenergicreceptor antagonist, and a dopaminergic agent.
 29. A method of treatingerectile dysfunction in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecomposition of claim 28.